| Role of the von Hippel-Lindau tumour suppressor protein in the regulation of HIF-1alpha and its oxygen-regulated transactivation domains at high cell density. | |
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MedLine Citation:
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PMID: 15750626 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hypoxia-inducible factor-1alpha (HIF-1alpha) induction and associated transcription were investigated during high cell density, focusing on the negative regulator of HIF-1alpha expression, the von Hippel-Lindau (VHL) protein. In 293T and HeLa cells, HIF-1alpha protein levels and associated transcription were induced as cells approached confluence. To determine whether these changes were due to a deficit in nuclear VHL-mediated ubiquitination of HIF-1alpha at confluence, cells were stably transfected with VHL. Overexpression of VHL in 293T cells had no demonstrable effect on the induction and nuclear accumulation of HIF-1alpha during high cell density or associated transcription. Moreover, RCC cells stably transfected with full-length VHL failed to exhibit the cell-density-dependent induction of HIF-1alpha noted in other cell lines. Investigation of both N-terminal and C-terminal (aa 727-826) oxygen-regulated proline and asparagine hydroxylation of HIF-1alpha revealed that both are inhibited during high cell density, as determined by impaired capture of HIF-1alpha by VHL and enhanced C-terminal transactivation. Finally, cell-density-mediated induction of HIF-1alpha and GLUT1 in RCC cells could be completely reconstituted by mutations in VHL binding affinity, suggesting that cell-density dependent induction of HIF-1alpha and transactivation may underpin some of the deregulated gene expression observed in VHL disease. |
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Authors:
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Steve M Paltoglou; Ben J Roberts |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Oncogene Volume: 24 ISSN: 0950-9232 ISO Abbreviation: Oncogene Publication Date: 2005 May |
Date Detail:
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Created Date: 2005-05-26 Completed Date: 2005-06-09 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 8711562 Medline TA: Oncogene Country: England |
Other Details:
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Languages: eng Pagination: 3830-5 Citation Subset: IM |
Affiliation:
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School of Pharmaceutical, Molecular and Biomedical Sciences, University of South Australia, Reid Building, Frome Rd., Adelaide 5000, Australia. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cell Count Cell Line Glucose Transporter Type 1 Humans Hypoxia-Inducible Factor 1, alpha Subunit Monosaccharide Transport Proteins / biosynthesis Response Elements / physiology Transcription Factors / biosynthesis* Transcriptional Activation* Tumor Suppressor Proteins / physiology* Ubiquitin-Protein Ligases / physiology* Von Hippel-Lindau Tumor Suppressor Protein |
| Chemical | |
Reg. No./Substance:
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0/Glucose Transporter Type 1; 0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Monosaccharide Transport Proteins; 0/SLC2A1 protein, human; 0/Transcription Factors; 0/Tumor Suppressor Proteins; EC 6.3.2.19/Ubiquitin-Protein Ligases; EC 6.3.2.19/VHL protein, human; EC 6.3.2.19/Von Hippel-Lindau Tumor Suppressor Protein |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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